Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, salts of 7-isoindolinequinolonecarboxylic acids, hydrates thereof, and composition containing the same as active ingredient

Abstract

This invention relates to processes for producing a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1] which is useful as an antibacterial agent, and an intermediate thereof:wherein R1 represents a hydrogen atom or a carboxyl-protecting group; R2 represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R3 represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R4 represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane group together with the carbon atom to which R4 bonds; R5 represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R6 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or C-R7 in which R7 represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group, and to a salt of a 7-isoindoline-quinolonecarboxylic acid represented by the general formula [1], a hydrate thereof and a composition comprising them as an active ingredient.

What is claimed is:  
     
       1. A process for producing a 7-isoindolinequinolonecarboxylic acid derivative or its salt, represented by the general formula [1]:                    
       wherein R 1  represents a hydrogen atom or a carboxyl-protecting group; R 2  represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R 3  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups or protected or unprotected or substituted or unsubstituted amino groups; R 4  represents at least one group selected from hydrogen atom, halogen atom, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group or groups each forming a cycloalkane ring together with the carbon atom to which R 4  bonds; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R 6  represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or C—R 7  in which R 7  represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group, comprising: 
       reacting, in the presence of metallic palladium an isoindoline-5-boronic acid derivative represented by the following general formula [2] or its salt:                    
       wherein R 3 , R 4  and R 5  have the same meanings as mentioned above; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, 
       with a 7-leaving group-substituted quinolonecarboxylic acid represented by the following general formula [3] or its salt:                    
       wherein R 1 , R 2 , R 6  and A have the same meanings as mentioned above; and X 2  represents a leaving group. 
     
     
       2. A process for producing a 7-isoindolinequinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt:                    
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, obtained by reacting a phenylalkylamine derivative represented by the general formula [10] or its salt:                    
       wherein R 4a  has the same meaning as mentioned above; and R 5a  represents an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, with carbon dioxide, a halogenated formic acid ester or a carbonic acid ester in the presence of a base to form a 2-aminoalkylbenzoic acid derivative represented by the general formula [9] or its salt:                    
       wherein R 4a  and R 5  have the same meanings as mentioned above; and R 10  represents a hydrogen atom or a carboxyl-protecting group, subsequently subjecting the 2-aminoalkylbenzoic acid derivative or its salt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acid derivative represented by the general formula [8] or its salt:                    
       wherein R 4a , R 5  and R 10  have the same meanings as mentioned above; and X 1  represents a halogen atom, subsequently subjecting the 2-aminoalkyl-5-halogenobenzoic acid derivative or is salt to reduction reaction to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivative represented by the following general formula [6] or its salt:                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, and thereafter subjecting the 2-aminoalkyl-5-halogenobenzyl alcohol derivative or its salt to ring-closing reaction to obtain a 1-alkyl-5-halogenoisoindoline derivative represented by the general formula [4a] or its salt:                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above and then subjecting the 1-alkyl-5-halogenoisoindoline derivative or its salt to borodation, 
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt:                    
       wherein R 1 , R 2 , R 6  and A have the same meanings as mentioned above and X 3  represents a halogen atom, 
       the compound represented by the general formula [1a] or its salt is                    
       wherein R 4a , R 1 , R 2 , R 5 , R 6  and A have the same meanings as mentioned above. 
     
     
       3. A process for producing a 7-isoindolinequinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt:                    
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, obtained by reacting a phenylalkylamine derivative represented by the general formula [10] or its salt:                    
       wherein R 4a  has the same meaning as mentioned above; and R 5a  represents an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, with carbon dioxide, a halogenated formic acid ester or a carbonic acid ester in the presence of a base, to obtain a 2-aminoalkylbenzoic acid derivative represented by the general formula [9] or its salt:                    
       wherein R 4a  and R 5  have the same meanings as mentioned above; and R 10  represents a hydrogen atom or a carboxyl-protecting group, subsequently subjecting the 2-aminoalkylbenzoic acid derivative or its salt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acid derivative represented by the general formula [8] or its salt:                    
       wherein R 4a , R 5  and R 10  have the same meanings as mentioned above; and X 1  represents a halogen atom, subsequently subjecting the 2-aminoalkyl-5-halogenobenzoic acid derivative or is salt to ring-closing reaction to obtain a 1-alkyl-3-oxo-5-halogenoisoindoline derivative represented by the general formula [7] or its salt:                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, subsequently subjecting the 1-alkyl-3-oxo-5-halogenoisoindoline derivative or its salt to reduction reaction to obtain a 1-alkyl-5-halogenoisoindoline derivative represented by the general formula [4a] or its salt:                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, and then subjecting the 1-alkyl-5-halogenoisoindoline derivative or its salt to borodation, 
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt:                    
       wherein R 1 , R 2 , R 6  and A have the same meanings as mentioned above and X 3  represents a halogen atom, and 
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt:                    
       wherein R 4a , R 1 , R 2 , R 5 , R 6  and A have the same meanings as mentioned above. 
     
     
       4. A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt:                    
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R 8  and R 9  represent hydrogen atoms or lower alkyl groups or form a ring comprising the boron atom when taken together, obtained by preparing a compound represented by the general formula [4a] or its salt                    
       wherein R 4a  represents an alkyl group; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X 1  represents a halogen atom, obtained by reacting a 4-halogenobenzylamine derivative represented by the general formula [12] or its salt:                    
       wherein R 4a  and X 1  have the same meanings as mentioned above; and R 5b , R 5c  and R 5d  may be the same or different and each represents an alkyl group, with formaldehyde or its derivative in the presence of an aryllithium to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivative represented by the general formula [6] or its salt;                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above, subsequently introducing a leaving group thereinto to obtain a 2-aminoalkyl-5-halogenobenzyl derivative represented by the general formula [1] or its salt:                    
       wherein R 4a , R 5  and X 1  have the same meanings as mentioned above; and Y represents a leaving group, and subsequently subjecting the 2-aminoalkyl-5-halogenobenzyl derivative to ring-closing reaction in the presence of a base, and subjecting the compound represented by the general formula [4a] or its salt to borodation, and 
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt:                    
       wherein R 4a , R 1 , R 2 , R 5 , R 6  and A have the same meanings as mentioned above. 
     
     
       5. A process for producing a 7-isoindolinequinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3a] or its salt:                    
       wherein R 1b  represents a carboxyl-protecting group; R 2a  represents a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group; and R 7a  represents a substituted or unsubstituted alkyl group, obtained by reacting a 2,4-dibromo-3-hydroxybenzoic acid ester represented by the general formula [13] or its salt:                    
       wherein R 1a  a represents a carboxyl-protecting group, with a compound represented by the general formula [14]: 
       
         
           R 7a —X  [14] 
         
       
       wherein R 7a  has the same meaning as mentioned above; and X represents a halogen atom, to obtain a 3-alkoxy-2,4-dibromobenzoic acid ester represented by the general formula [15] or its salt:                    
       wherein R 1a  and R 7a  have the same meanings as mentioned above, subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid ester to elimination reaction of the carboxyl-protecting group to obtain a 3-alkoxy-2,4-dibromobenzoic acid represented by the general formula [16] or its salt:                    
       wherein R 7a  has the same meaning as mentioned above, subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid to ketoesterification reaction to obtain a 3-alkoxy-2,4-dibromobenzoylacetic acid ester represented by the general formula [17] or its salt:                    
       wherein R 1b  represents a carboxyl-protecting group; and R 7a  has the same meaning as mentioned above, subsequently reacting the 3-alkoxy-2,4-dibromobenzoylacetic acid ester with an orthoester or an acetal, then reacting the reaction product with a compound represented by the general formula [18] or its salt: 
       
         
           R 2a —NH  [18] 
         
       
       wherein R 2a  has the same meaning as mentioned above, to obtain a 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester represented by the general formula [19] or its salt:                    
       wherein R 1b , R 2a  and R 7a  have the same meanings as mentioned above, and thereafter subjecting the 2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester to ring-closing reaction, and 
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1b] or its salt:                    
       wherein R 1 , R 2a , R 3 , R 4 , R 5  and R 7a  have the same meanings as mentioned above. 
     
     
       6. A process for producing a 7-isoindolinequinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein R 5  represents a hydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group. 
     
     
       7. (R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate. 
     
     
       8. (R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate. 
     
     
       9. A composition comprising an active ingredient selected from the group consisting of (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate and (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate, and an inactive ingredient. 
     
     
       10. The composition according to  claim 9 , wherein the inactive ingredient is a carrier acceptable as a preparation. 
     
     
       11. A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt,  
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt, and  
       the compound represented by the general formula or its salt is a compound represented by the general formula [1a] or its salt.  
     
     
       12. A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt,  
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3b] or its salt, and  
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt.  
     
     
       13. A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [2] or its salt is a compound represented by the general formula [2b] or its salt obtained by preparing a compound represented by the general formula [4a] or its salt and subjecting the compound represented by the general formula [4a] or its salt to borodation, and  
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1a] or its salt.  
     
     
       14. A process for producing a 7-isoindoline-quinolonecarboxylic acid derivative or its salt according to  claim 1 , wherein 
       the compound represented by the general formula [3] or its salt is a compound represented by the general formula [3a] or its salt, and  
       the compound represented by the general formula [1] or its salt is a compound represented by the general formula [1b] or its salt.